The main goal of this work is to understand the role of small RNAs and ribonucleoprotein (RNP) complexes in creating innate immune response to viral infections. The human host is invaded by a wide range of microbial pathogens and has evolved a number of defensive mechanisms to survive these infections. In addition to adaptive immunity, it is becoming increasing clear that innate immunity plays an important role in protecting host organisms from infections. A number of pathogen-associated innate immune responses have been previously identified. Recent studies have revealed that an innate immune response mechanism against viral infections involve a protein family, APOBEC3 (apolipoprotein B mRNA editing enzyme catalytic polypeptide 3). APOBEC3 family proteins can restrict replication of exogenous retroviruses as well as well as Hepatitis B, a DNA virus that replicates through an RNA intermediate and inhibits replication of retrotransposons. APOBEC3G protein exhibits the most potent block to HIV-1 replication. A second innate immune mechanism of defense against viral infections in plants and invertebrates involves RNAi. However, very little is known about the RNA-based antiviral immunity mechanisms in mammals. In this proposed work, we will define the role of small RNAs, RNP complexes containing APOBEC3G, and their subcellular context in modulating the HIV-1 life cycle. We believe that these studies will provide fundamental insight into the function of APOBEC3 proteins and into the mechanism of RNA-based innate immunity against retroviruses. Small molecules that interfere with interactions between a viral protein and the A3G RNPs could provide new drugs for AIDS therapy. PUBLIC HEALTH RELEVANCE: The human host is invaded by a wide range of microbial pathogens and has evolved a number of defensive mechanisms to survive these infections. Recent studies have revealed that a host protein, APOBEC3G, exhibits the most potent block to HIV-1 replication. A second innate immune mechanism of defense against viral infections in plants and invertebrates involves RNAi. Experiments in the proposed work would decipher the mechanisms of these two innate immune responses to HIV-1 infection. Results of these studies would offer tremendous potential to not only explore host-pathogen interactions at the mechanistic levels, but also to develop new therapeutics for viral infections. Small molecules that interfere with interactions of a viral protein with APOBEC3G complexes could provide new drugs for AIDS therapy. In addition, cellular genes that are modulated by RNAI machinery during HIV infection would identify new candidates for drug development.